Jiangsu Provincial Key Lab of Cardiovascular Diseases and Molecular Intervention, Department of Pharmacology, Nanjing Medical University, Nanjing 210029, People's Republic of China.
J Mol Endocrinol. 2011 Sep 7;47(2):219-27. doi: 10.1530/JME-11-0048. Print 2011 Oct.
Urocortin (Ucn), a corticotropin-releasing factor (CRF)-related neuropeptide binding both CRF type 1 receptor (CRFR1) and CRFR2, has recently been found in prostate cancer. However, no report has yet been known to elucidate the roles of Ucn in prostate cancer via the two receptors. In this study, the expression of both CRFR1 and CRFR2 in the mouse prostate cancer cell line RM-1 were detected and cellular apoptosis was monitored in the presence of CRF or Ucn2, the CRFR1- and CRFR2-selective agonist respectively. CRF promoted apoptosis while Ucn2 exerted the opposite effect. CRF reduced Bcl-2 expression, induced Bax expression, and hyperpolarized the mitochondrial membrane potential to activate caspase-9. On the contrary, Ucn2 increased Bcl-2 expression and decreased Bax expression, in which phosphorylation of Akt and cyclic AMP response element-binding (CREB) was involved. Pretreatment with phosphatidylinositide 3-kinase/Akt inhibitor (LY-294002) prior to Ucn2 led to downregulation of CREB phosphorylation and hence reduced Bcl-2 expression. These effects of CRF and Ucn2 were abolished by antalarmin (Anta) and antisauvagine-30, the CRFR1- and CRFR2-selective antagonist respectively. In LNCaP cell line, similar effects on cell apoptosis by CRF and Ucn2 were observed. In summary, our results demonstrated CRFR1 and CRFR2 expression in prostate cancer and indicated the opposite apoptotic roles of the two different CRFRs. These data may contribute to uncovering the pathophysiological function of endogenous Ucn in prostate tumorigenesis and progression.
尿皮质素 (Ucn) 是一种促肾上腺皮质激素释放因子 (CRF) 相关的神经肽，可与 CRF 型 1 受体 (CRFR1) 和 CRF 型 2 受体 (CRFR2) 结合，最近在前列腺癌中被发现。然而，目前尚无报道阐明 Ucn 通过这两种受体在前列腺癌中的作用。在本研究中，检测了小鼠前列腺癌细胞系 RM-1 中 CRFR1 和 CRFR2 的表达，并在存在 CRF 或 Ucn2（分别为 CRFR1 和 CRFR2 选择性激动剂）时监测细胞凋亡。CRF 促进细胞凋亡，而 Ucn2 则产生相反的作用。CRF 降低 Bcl-2 的表达，诱导 Bax 的表达，并使线粒体膜电位去极化以激活 caspase-9。相反，Ucn2 增加了 Bcl-2 的表达，降低了 Bax 的表达，其中涉及 Akt 和环磷酸腺苷反应元件结合 (CREB) 的磷酸化。在 Ucn2 预处理之前用磷脂酰肌醇 3-激酶/Akt 抑制剂 (LY-294002) 处理，导致 CREB 磷酸化下调，从而降低了 Bcl-2 的表达。CRF 和 Ucn2 的这些作用被 Anta 和 antisauvagine-30（分别为 CRFR1 和 CRFR2 选择性拮抗剂）所消除。在 LNCaP 细胞系中，也观察到了 CRF 和 Ucn2 对细胞凋亡的类似影响。总之，我们的结果表明前列腺癌中存在 CRFR1 和 CRFR2 的表达，并表明这两种不同的 CRFR 具有相反的促凋亡作用。这些数据可能有助于揭示内源性 Ucn 在前列腺肿瘤发生和进展中的病理生理功能。
